A d ren a l D i s o rd e r s

in Rheumatology
Michelle J. Ormseth,

MD

a,

*, John S. Sergent,

MD

KEYWORDS

Adrenal
Cushing syndrome

Hypothalamic pituitary adrenal axis
Glucocorticoid

Rheumatologic
Autoimmune

Knowledge of both adrenal insufficiency and Cushing syndrome are important in the
care of patients with rheumatologic disease due to clinical similarities in relation to
glucocorticoid in rheumatologic diseases. Difficulties in differentiating between
adrenal insufficiency and active or worsening disease often arise when glucocorticoids are tapered in patients with conditions such as vasculitis and polymyositis. In
addition there are striking similarities with adrenal insufficiency and diseases such
as fibromyalgia syndrome and polymyalgia rheumatica. Similarly, the proximal muscle
symptoms of Cushing syndrome can be mistaken for several other disorders such as
polymyositis. Osteoporosis is a major concern in patients with endogenous and glucocorticoid-induced Cushing syndrome.

ADRENAL INSUFFICIENCY
Definition

Adrenal insufficiency is classified into three subtypes based on where the abnormality
is based in the hypothalamic pituitary adrenal (HPA) axis. Primary insufficiency is
caused by adrenal gland damage. The secondary form is related to insufficient corticotrophin (ACTH) from the pituitary gland. The tertiary form is related to insufficient
corticotrophin-releasing hormone (CRH) from the hypothalamus.
Acute adrenal insufficiency, or adrenal crisis, is severe and characterized by shock.
This is often related to mineralocorticoid deficiency, but not always in severe cases
related to exogenous glucocorticoid withdrawal. Chronic primary adrenal insufficiency

The authors have nothing to disclose.

a
Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University
Medical Center, Vanderbilt University School of Medicine, 1161 21st Avenue South, T-3219
MCN, Nashville, TN 37232-2681, USA
b
Department of Internal Medicine, Vanderbilt University Medical Center, 1161 21st Avenue
South, D-3100 MCN, Nashville, TN 37232-2358, USA
* Corresponding author.
E-mail address: Michelle.ormseth@vanderbilt.edu
Rheum Dis Clin N Am 36 (2010) 701712
doi:10.1016/j.rdc.2010.09.005
rheumatic.theclinics.com
0889-857X/10/$ see front matter 2010 Elsevier Inc. All rights reserved.

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Ormseth & Sergent

is related to deficiency of glucocorticoid, mineralocorticoid, and even androgen deficiency in women.

Causes and Associations with Rheumatologic Disease

Primary adrenal insufficiency, or Addison disease, initially was most commonly related
to tuberculosis, but now is typically caused by autoimmune adrenalitis in the Western
world (69% to 91.2%).1,2 Additionally, in one retrospective study, a concomitant autoimmune disorder was seen in nearly 50% of patients with autoimmune adrenalitis,
including most commonly autoimmune thyroid disease and vitiligo, but less commonly
Sjogren syndrome.1 Although concomitant connective tissue disease is only occasionally reported in literature (in addition to Sjogren syndrome), there are also reports
of systemic lupus erythematosis,3 rheumatoid arthritis,4 systemic sclerosis,5,6
Takayasu arteritis, and ankylosing spondylitis.7 More frequently thrombosis of the
adrenal gland, caused by antiphospholipid antibody syndrome, is seen.812 Polyglandular autoimmune syndrome type II (APSII) has some reported association with
rheumatoid arthritis13 and Sjogren syndrome.14 The reported association with rheumatologic disease is infrequent and may be coincidence; association with polyglandular autoimmune syndrome type I is not reported. This may be because of differences
in HLA type.15
Secondary adrenal insufficiency can be related to the destruction of the pituitary
gland or deficiency of ACTH. Classically, this is associated with hemorrhage of the
pituitary gland, or thrombosis such as seen when sarcoidosis affects the pituitary
gland.16 There have been a few reports of opiate induced secondary adrenal insufficiency.17,18 Glucocorticoid use can cause secondary or tertiary adrenal insufficiency.
Tertiary adrenal insufficiency is most commonly related to withdrawal of glucocorticoids. Glucocorticoid-induced adrenal insufficiency can be caused by several mechanisms, including decreased hypothalamic synthesis of CRH, blockade of the actions
of CRH on the anterior pituitary, and, after prolonged or profound deficiency of ACTH,
adrenal atrophy.19,20
Adrenal crisis can occur in patients with all forms of adrenal insufficiency, but more
often is associated with primary adrenal insufficiency. The trigger can be infection or
other major stress with no or insufficient glucocorticoid intake. Certainly, bilateral
adrenal hemorrhage or infarction and pituitary infarction can cause this also. Abrupt
discontinuation of corticosteroids and inadequate supplementation in stress are other
causes of adrenal crisis.
Signs and Symptoms

The symptoms of adrenal crisis are more severe than chronic adrenal insufficiency.
The distinguishing feature of adrenal crisis is shock, and other signs and symptoms
depend on whether the patient has underlying primary or secondary adrenal insufficiency. Table 1 displays the signs and symptoms of adrenal insufficiency.
Chronic adrenal insufficiency is more difficult to diagnose, as presenting symptoms
can be vague. A recent comprehensive review of cases of hypoadrenalism reported in
literature since its characterization over 150 years ago showed that the most common
symptoms of adrenal insufficiency are arthralgias, myalgias, back pain, and
decreased joint movement. Those with primary adrenal insufficiency additionally
frequently had fatigue, gastrointestinal symptoms, hyperpigmentation, weight loss,
hypotension, and postural dizziness.21 Painful lower extremity flexion contractures
of the muscles of the pelvic girdle, hips, and knees are common signs in autoimmune
primary adrenal insufficiency and pituitary causes are often seen with isolated deficiency of ACTH.2224

Adrenal Disorders in Rheumatology

Table 1
Similarities between adrenal insufficiency and fibromyalgia syndrome
Primary

Secondary/
Glucocorticoid- Induced

Fibromyalgia

Myalgia

xxx

xxx

xxx

Arthralgia

xxx

xxx

xxx

Back pain

xxx

xx

Fatigue

xxx

xxx

xxx

Gastrointestinal symptomsa

xx

Postural dizziness

Symptoms

xxb

Hypogonadism
Psychiatric

Poor sleep

xxx
xxx

Signs
Hyperpigmentation

xx

Weight loss

xx

Flexion contracture

xc

xxc

Hypotension

xx

Hyponatremia

xx

Hyperkalemia

xx

Hypoglycemia
Anemia
a
b
c

x
xx

Gastrointestinal symptoms include nausea, vomiting, diarrhea.

In the setting of hypopituitarism.
In general associated with autoimmune and pituitary causes.

Rheumatology Mimickers and Methods of Differentiation

Adrenal insufficiency can look much like fibromyalgia syndrome. Table 1 compares
various forms of adrenal insufficiency and fibromyalgia syndrome. Widespread pain
with emphasis on muscles and joints is most common complaint in fibromyalgia
patients.25 In addition to more commonly recognized symptoms of pain, stiffness,
fatigue, sleep disturbance, and mood disorder of fibromyalgia syndrome,26 patients
can have disabling dizziness.27 The important differentiating factors for these diseases
are the physical signs of disease such as electrolyte abnormalities, flexion contractures,
and hypotension; however, these are not always present in adrenal insufficiency.
Polymyalgia rheumatica (PMR) can look quite similar to adrenal insufficiency. With
stiffness, pain, malaise, weight loss, and fever, the best differentiating factor is the
elevated acute phase reactants in polymyalgia rheumatica.
When considering the differential diagnosis of arthralgia and myalgia it is important
to recall that adrenal insufficiency is the only one characterized by predominant lower
limb pain.21 This difference may be helpful when proposing an appropriate initial
workup.
Glucocorticoid-induced Adrenal Insufficiency

A major concern to physicians is glucocorticoid-induced adrenal insufficiency caused

by HPA axis suppression. In the course of steroid taper, a patient may develop steroid

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withdrawal syndrome or true adrenal insufficiency. The symptomatology is very

similar, but the withdrawal syndrome displays normal HPA axis testing, and these
patients do not develop adrenal crisis.28 The symptoms can develop despite supraphysiologic steroid dose.29 The underlying cause of the withdrawal syndrome may
be related to elevated interleukin (IL)-6.30
The symptoms of glucocorticoid-induced adrenal insufficiency are listed in Table 1,
but it can notably manifest as adrenal crisis. It can occur in the setting of medical and
surgical stress and also with concomitant use of certain medications, whether it be
through increased steroid metabolism with rifampicin or decreased absorption with
bile acid sequestrants. Table 2 shows several culprit medications.
Dose, duration of use, and potency of the glucocorticoid factor into the risk of HPA
axis suppression. However, even inhaled corticosteroids, if abruptly withdrawn, can
promote adrenal insufficiency.31 If possible to do, alternate-day dosing of oral glucocorticoids may be helpful to prevent suppression of the HPA axis.32
There have been no prospective studies to determine the best method of steroid
taper. Although it has not been tested in randomized placebo-controlled trial, the
authors recommend when tapering high-dose glucocorticoids that at the point
when taper can be initiated, gradually taper prednisone equivalent to 5 mg over
6 months then decrease by 1 mg per month.
Diagnosis of Adrenal Insufficiency

There are several tests involved in the evaluation of adrenal insufficiency. Baseline
morning (68 am) cortisol level less than 83 nmol/L or less than 3 mg/dL is diagnostic
of adrenal insufficiency, whereas levels greater than 550 nmol/L or 20 mg/dL at anytime
exclude it.33 If initial evaluation does not provide a diagnosis, the short 250 mg ACTH
(cosyntropin) stimulation test may be performed; after baseline cortisol level is
obtained, 250 mg ACTH is administered, and cortisol is measured 30 to 60 minutes
later. If the adrenal gland cannot produce the normal 18 mg/dL or 500 nmol or greater
response, it is indicative of primary adrenal insufficiency or other forms after functional
adrenal gland atrophy occurs.34 This test can be normal in central adrenal insufficiency, however. The insulin-induced hypoglycemia test can be helpful to determine
if the patient has a deficiency in ACTH, but can be dangerous given the induction of
hypoglycemia in particularly the elderly and those with cardiovascular disease.
Thus, the CRH stimulation test can be used alternatively, but it can be costly. An overnight metyrapone test can help to diagnose secondary adrenal insufficiency caused
by disruption of cortisol synthesis, but obtaining the drug can be difficult. Finally,

Table 2
Medications that change the metabolism or availability of glucocorticoids
Decrease GC Levels

Increase GC Levels

Barbiturates80

Antiretrovirals, especially ritonavir81

Bile acid sequestrants82

Azole antifungals, fluconazole

Mitotane83

Clarithromycin84

Primidone85

Estrogen derivatives

Rifampicin8688

Itraconazole89

Somatropin90

Macrolides except for azithromycin and spiramycin

Nondihydropyridine calcium channel blockers

Abbreviation: GC, glucocorticoid.

Adrenal Disorders in Rheumatology

the low-dose ACTH stimulation can be performed, but it may not supply much more
information compared with the high-dose test.35
Special considerations are necessary if the patient is taking glucocorticoids. Given
the limited half-life of the drugs, testing can be performed before administration of
daily morning glucocorticoid dose. In general, if there is difficulty tapering the glucocorticoid dose below physiologic levels because of symptoms suggestive of adrenal
insufficiency, evaluation via the 250 mg ACTH stimulation test may be helpful, and, if
necessary, the CRH stimulation test may be used to confirm.36
HPA Axis Dysfunction in Rheumatologic Disease

There has been the suggestion that inadequate HPA axis response to a stress and
chronic exposure to the stressor may be contributing factors to autoimmune
disease.37 Rheumatoid arthritis patients have inappropriately low cortisol levels for
their inflammatory status and have low adrenal androgens.38,39 Similarly, HPA axis
abnormalities have been shown in Sjogren syndrome and systemic lupus erythematosus,40,41 and seem to promote chronic inflammation.42 There are low dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) levels in Sjogren syndrome patients,
and DHEA supplementation was shown to slightly improve symptoms of dry mouth
in one study.43
Low serum DHEA levels are common in systemic lupus erythematosus, and low
levels correlate with active disease.44 Studies looking at supplementation of DHEA
are conflicting. A 6-month open-label study looking at lupus patients with mild-tomoderate disease showed significant reduction in Systemic Lupus Erythematosus
Activity Index (SLEDAI) (from 10.0  2.9 to 4.9  1.7, P 5 .04) and a decrease in daily
corticosteroid requirement.45 However, a 3-month double-blind randomized placebocontrolled trial of patients with mild-to-moderate lupus showed no statistically significant difference in the SLEDAI or corticosteroid use.46 Another randomized, doubleblind placebo-controlled trial of patients with active lupus showed that supplementation with DHEA 200 mg/d resulted in a sustained reduction of prednisone dose in 51%
in the treatment group versus 29% in the placebo group (P 5 .031).47 The same conflicting information is present in looking at the benefit to fatigue and well-being.48,49
PMR, as mentioned, has major presenting symptomatic similarities to adrenal insufficiency as well as resolution of symptoms with administration of glucocorticoids. It
has been asserted that PMR is an HPA-axis driven disease.50 Given inflammatory
status, patients with PMR have low serum cortisol levels on or off corticosteroids.51
A study evaluating the HPA axis in PMR patients showed that these patients have
lower cortisol and adrenal androgen, DHEAS, and this was related to abnormal
adrenal response to ACTH stimulation.52
CUSHING SYNDROME
Definition and Causes

Cushing syndrome is a term given to a collection of manifestations caused by hypercortisolism. The most common cause is exogenous glucocorticoid administration.
Endogenous Cushing syndrome is far less common. Causes include Cushing disease,
an overproduction of ACTH caused by pituitary adenoma, ectopic ACTH production,
or overproduction of cortisol in the adrenal glands. Under-recognized sources of
Cushing syndrome include inhaled53 and topical preparations,54 intra-articular joint
injections,55 and even Chinese herbal medicines, which may contain various types
of glucocorticoids.56 Table 2 shows several medications that can increase exogenous
glucocorticoid levels, increasing the risk of Cushing syndrome.

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Signs and Symptoms

The signs and symptoms of Cushing syndrome include

Central obesity with moon face and buffalo hump
Thin skin
Large purple striae
Cataracts
Poor wound healing
Lower extremity edema
Spontaneous tendon rupture, muscle wasting, particularly in the lower proximal
limbs
Osteoporosis
Insulin resistance
Hypertension and cardiovascular disease
Arterial and venous thrombosis
Psychiatric disturbance
Hirsutism
Gonadal dysfunction (related to adrenocortical androgens).5760
Polyarthropathy can develop in Cushing syndrome, but it most likely related to avascular necrosis of multiple joints, which is more common in glucocorticoid-associated
than spontaneous Cushing syndrome.61,62 Endogenous Cushing syndrome can mask
or induce remission in steroid-responsive disease such as rheumatoid arthritis.63,64
Some patients with Cushing disease can have cyclical episodes of active hypercortisolism or just have one predominant feature.65 This can cause delays and confusion in
diagnosis.
Interestingly, while patients with endogenous Cushing syndrome have increased
cardiovascular disease, the use of glucocorticoids does not appear to be associated
with increased risk of cardiovascular disease, at least in patients with polymyalgia
rheumatica, rheumatoid arthritis, and systemic lupus erythematosus.6668
Dose, duration of use, and potency of the glucocorticoid factor into the risk of glucocorticoid-induced myopathy. Short-term high-dose corticosteroid use results in acute
diffuse myopathy, atrophy, and even rhabdomyolysis.69 Chronic use results in chronic
myopathy manifested with proximal muscle weakness. The equivalent of 10 mg prednisone daily is an unusual cause of myopathy, but doses of 40 to 60 mg/d can cause
weakness within 2 weeks.70 Fluorinated glucocorticoid preparations are more often
associated with myopathy than nonfluorinated glucocorticoid preparations.71
Osteoporosis

Osteoporosis is a considerable threat in Cushing syndrome. Even subclinical Cushing

syndrome can result in osteoporosis.72 The relative risk of low-energy fractures in
patients with endogenous Cushing syndrome was 5.4 compared with controls, but
there was a sharp decline in risk after treatment.73 Despite that sharp decline, the
duration of subsequent glucocorticoid replacement is a stronger predictor of low
bone density than the duration of untreated Cushing syndrome.74
Not only does glucocorticoid use, particularly high-dose glucocorticoid use, cause
rapid loss of trabecular bone mineral density, but it also causes loss of lean body
mass, which together increase the risk of fracture.75 This bone loss is rapid in the first
6 months of treatment, declining by approximately 5% in the first year, but subsequent
loss is 1% to 2% per year.76 In one study, this translated into 17% of patients developing a vertebral fracture in the first year of glucocorticoid use.77 While alternate-day

Adrenal Disorders in Rheumatology

Table 3
Differential diagnosis of proximal muscle symptoms and method of differentiation

Cushing syndrome

Creatine Kinase

Pain

Weakness

nl/sl[

Polymyositis/Dermatomyositis

Polymyalgia rheumatica

nl

Hypothyroidism91

Vitamin D deficiency92

nl

Fibromyalgia syndrome

nl

Statin myopathy

Myasthia gravis

nl

Muscular dystrophy

dosing possibly may help prevent adrenal insufficiency, it does not help prevent bone
loss.78
Rheumatology Mimickers and Methods of Differentiation

Important to the differential diagnosis of proximal muscle weakness are Cushing

syndrome, both endogenous and glucocorticoid-induced, and inflammatory myopathy such as polymyositis. Table 3 shows a comparison of disorders causing proximal
muscle symptoms. In particular, differentiating between active polymyositis and
glucocorticoid-induced myopathy in a patient with known polymyositis can be very
difficult. Tapering the glucocorticoid dose and monitoring serial urinary creatine may
be helpful, as this will decrease with the discontinuation of steroids in the setting of
glucocorticoid-induced myopathy as opposed to increasing with polymyositis.79
Diagnosis of Cushing Syndrome

After exclusion of exogenous glucocorticoid use, the recommendation from the Endocrine Society is to evaluate the patient with a high diagnostic accuracy test. If this is
abnormal, the patient should be referred to endocrinologist for further evaluation.58
The initial tests include late night salivary cortisol (at least two measurements), urinary
free cortisol (at least two measurements), and a low-dose dexamethasone suppression test.
SUMMARY

Understanding adrenal disorders, whether endogenous or related to glucocorticoid

use is important to the day-to-day care of patients with rheumatologic disease.
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